Embryonic Stem Cell-Derived L1 Overexpressing Neural Aggregates Enhance Recovery after Spinal Cord Injury in Mice

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Abstract

An obstacle to early stem cell transplantation into the acutely injured spinal cord is poor survival of transplanted cells. Transplantation of embryonic stem cells as substrate adherent embryonic stem cell-derived neural aggregates (SENAs) consisting mainly of neurons and radial glial cells has been shown to enhance survival of grafted cells in the injured mouse brain. In the attempt to promote the beneficial function of these SENAs, murine embryonic stem cells constitutively overexpressing the neural cell adhesion molecule L1 which favors axonal growth and survival of grafted and imperiled cells in the inhibitory environment of the adult mammalian central nervous system were differentiated into SENAs and transplanted into the spinal cord three days after compression lesion. Mice transplanted with L1 overexpressing SENAs showed improved locomotor function when compared to mice injected with wild-type SENAs. L1 overexpressing SENAs showed an increased number of surviving cells, enhanced neuronal differentiation and reduced glial differentiation after transplantation when compared to SENAs not engineered to overexpress L1. Furthermore, L1 overexpressing SENAs rescued imperiled host motoneurons and parvalbumin-positive interneurons and increased numbers of catecholaminergic nerve fibers distal to the lesion. In addition to encouraging the use of embryonic stem cells for early therapy after spinal cord injury L1 overexpression in the microenvironment of the lesioned spinal cord is a novel finding in its functions that would make it more attractive for pre-clinical studies in spinal cord regeneration and most likely other diseases of the nervous system.

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Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.

S Lee, N Lumelsky, L Studer … (2000)

Embryonic stem (ES) cells are clonal cell lines derived from the inner cell mass of the developing blastocyst that can proliferate extensively in vitro and are capable of adopting all the cell fates in a developing embryo. Clinical interest in the use of ES cells has been stimulated by studies showing that isolated human cells with ES properties from the inner cell mass or developing germ cells can provide a source of somatic precursors. Previous studies have defined in vitro conditions for promoting the development of specific somatic fates, specifically, hematopoietic, mesodermal, and neurectodermal. In this study, we present a method for obtaining dopaminergic (DA) and serotonergic neurons in high yield from mouse ES cells in vitro. Furthermore, we demonstrate that the ES cells can be obtained in unlimited numbers and that these neuron types are generated efficiently. We generated CNS progenitor populations from ES cells, expanded these cells and promoted their differentiation into dopaminergic and serotonergic neurons in the presence of mitogen and specific signaling molecules. The differentiation and maturation of neuronal cells was completed after mitogen withdrawal from the growth medium. This experimental system provides a powerful tool for analyzing the molecular mechanisms controlling the functions of these neurons in vitro and in vivo, and potentially for understanding and treating neurodegenerative and psychiatric diseases.

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Microglial control of neuronal death and synaptic properties.

Anne Roumier, Alain Bessis, D Bernard … (2007)

Microglia have long been characterized by their immune function in the nervous system and are still mainly considered in a beneficial versus detrimental dialectic. However a review of literature enables to shed novel lights on microglial function under physiological conditions. It is now relevant to position these cells as full time partners of neuronal function and more specifically of synaptogenesis and developmental apoptosis. Indeed, microglia can actively control neuronal death. It has actually been shown in retina that microglial nerve growth factor (NGF) is necessary for the developmental apoptosis to occur. Similarly, in cerebellum, microglia induces developmental Purkinje cells death through respiratory burst. Furthermore, in spinal cord, microglial TNFalpha commits motoneurons to a neurotrophic dependent developmental apoptosis. Microglia can also control synaptogenesis. This is suggested by the fact that a mutation in KARAP/DAP12, a key protein of microglial activation impacts synaptic functions in hippocampus, and synapses protein content. In addition it has been now demonstrated that microglial brain-derived neurotrophin factor (BDNF) directly regulates synaptic properties in spinal cord. In conclusion, microglia can control neuronal function under physiological conditions and it is known that neuronal activity reciprocally controls microglial activation. We will discuss the importance of this cross-talk which allows microglia to orchestrate the balance between synaptogenesis and neuronal death occurring during development or injuries. Copyright 2006 Wiley-Liss, Inc.

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Calbindin D-28k and parvalbumin in the rat nervous system.

M Celio (1990)

This paper describes the distribution of structures stained with mono- and polyclonal antibodies to the calcium-binding proteins calbindin D-28k and parvalbumin in the nervous system of adult rats. As a general characterization it can be stated that calbindin antibodies mainly label cells with thin, unmyelinated axons projecting in a diffuse manner. On the other hand, parvalbumin mostly occurs in cells with thick, myelinated axons and restricted, focused projection fields. The distinctive staining with antibodies against these two proteins can be observed throughout the nervous system. Calbindin D-28k is primarily associated with long-axon neurons (Golgi type I cells) exemplified by thalamic projection neurons, strionigral neurons, nucleus basalis Meynert neurons, cerebellar Purkinje cells, large spinal-, retinal-, cochlear- and vestibular ganglion cells. Calbindin D-28k occurs in all major pathways of the limbic system with the exception of the fornix. Calbindin D-28k is, however, also found in some short-axon cells (Golgi type II), represented by spinal cord interneurons in layer II and interneurons of the cerebral cortex. It is also detectable in some ependymal cells and abundantly occurs in vegetative centres of the hypothalamus. The "paracrine core" of the nervous system and its adjunct (1985, Nieuwenhuys, Chemoarchitecture of the Brain. Springer, Berlin) is very rich in calbindin D-28k. The distribution of calbindin D-28k-positive neurons is very similar to that of the dihydroperydine subtype of calcium channels. Most of the cells containing calbindin D-28k are vulnerable to neurodegenerative processes. Parvalbumin-immunoreactive neurons have a different, and mostly complementary distribution compared with those which react with calbindin D-28k antisera, but in a few cases (Purkinje cells of the cerebellum, spinal ganglion neurons), both calcium-binding proteins co-exist in the same neuron. Many parvalbumin-immunoreactive cells in the central nervous system are interneurons (Golgi type II) and, to a lesser extent, long-axon cells (Golgi type I), whereas conditions are vice versa in the peripheral nervous system. Intrinsic parvalbuminic neurons are prominent in the cerebral cortex, hippocampus, cerebellar cortex and spinal cord. Long-axon parvalbumin-immunoreactive neurons are, for example, the Purkinje cells, neurons of the thalamic reticular nucleus, globus pallidus, substantia nigra (pars reticulata) and a subpopulation among large spinal-, retinal-, cochlear- and vestibular ganglion cells. Parvalbumin is rich in cranial nerve nuclei related to eye movements. In addition to nervous elements, parvalbumin immunoreactivity occurs in a few ependymal cells and in some pillar cells of the organ of Corti.(ABSTRACT TRUNCATED AT 400 WORDS)

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: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2011

Publication date (Electronic): 18 March 2011

Volume: 6

Issue: 3

Electronic Location Identifier: e17126

Affiliations

[1 ]Zentrum für Molekulare Neurobiologie Hamburg, Universitätskrankenhaus Hamburg-Eppendorf, Universität Hamburg, Hamburg, Germany

[2 ]Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany

[3 ]W. M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, New Jersey, United States of America

[4 ]Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

National Institute on Aging Intramural Research Program, United States of America

Author notes

* E-mail: melitta.schachner@ 123456zmnh.uni-hamburg.de (MS); c.bernreuther@ 123456uke.de (CB)

Conceived and designed the experiments: MS CB. Performed the experiments: YC JX GH IJ CB. Analyzed the data: YC JX GH IJ MS CB. Contributed reagents/materials/analysis tools: MS. Wrote the paper: YC MS CB.

Article

Publisher ID: PONE-D-10-04116

DOI: 10.1371/journal.pone.0017126

PMC ID: 3060805

PubMed ID: 21445247

SO-VID: 74df1038-2058-49c0-8765-20a993a83210

Copyright © Cui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Date received : 27 October 2010

Date accepted : 21 January 2011

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Pages: 15

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Embryonic Stem Cell-Derived L1 Overexpressing Neural Aggregates Enhance Recovery after Spinal Cord Injury in Mice

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Most cited references 53

Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.

Microglial control of neuronal death and synaptic properties.

Calbindin D-28k and parvalbumin in the rat nervous system.

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